Estrogen receptor alpha (ERa) and beta (ER[unreadable]) are members of the nuclear receptor superfamily and mediate the actions of estrogens. These receptors are involved in numerous and diverse physiological processes but also pathological conditions, including cancer. ERa and ER[unreadable] are distinct proteins encoded by two genes, and expressed in many tissues. Most studies have focused on the role of ERs in male and female reproductive tract development and function, the interest of our laboratory. Little is known about the actions of estrogens in non-reproductive organs, regulating immune modulation, maintenance of bone density, cardiovascular function, behavior, learning, memory, and adipogenesis. ERa and ER[unreadable] are not expressed by the same cell types during development and homeostasis. However, in estrogen-regulated pathological situations, such as breast cancer, both ERs are frequently co-expressed. Breast cancers that express both ERs have a better prognosis than those that express only ERa. The essential physiological functions of both ERs have been examined by gene deletion studies. However, few studies have investigated the in vivo consequences of ER over-expression. Ubiquitous over-expression of ERa in mice led to embryo lethality, limiting studies, whereas doxycycline-inducible over-expression of ERa was useful, but hindered by the small number of tissue-specific tetracycline transactivator transgenic mouse lines. Furthermore, no mouse models for ER[unreadable] over-expression have been reported. The lack of robust and flexible mouse models for conditional over-expression of ERa or ER[unreadable] is limiting progress in estrogen signaling research in multiple fields. Therefore, the objective of this proposal is to generate transgenic mice that can over-express ERa or ER[unreadable] at different levels in a Cre recombinase-dependent manner to investigate ER function in vivo and model ER over-expression pathologies. PUBLIC HEALTH RELEVANCE: Estrogen is a hormone that normally controls many different body functions but can also influence the progression of life-threatening diseases, including breast and prostate cancer. This hormone acts through receptors that regulate gene expression. This project will develop novel estrogen receptor transgenic mouse models to activate estrogen-regulated gene expression in different organs to study the diverse physiological and pathological processes controlled by estrogen.